It is known that biological substances of natural origin can be obtained from the glands of land and aquatic animals and that such substances can be used to treat hormonal deficiencies in man and other animals. Among such substances is the hormone calcitonin. This hormone has been found to be particularly useful in the treatment of Paget's Disease (See the article by DeRose et al entitled "Treatment of Paget's Disease with Calcitonin" in Seminars in Drug Treatment, Vol. 2, No. 1.
Calcitonins have been obtained from bovine, porcine and human sources and these have been found to exhibit hormonal action when administered to animals or to man. The most active of the calcitonins has been obtained from salmon fishes. (Copp, D. H., Parkes, C. O., and O'Dor, R. K., Feder. Proc. 28/2, 413 [1969]). The calcitonin extract obtained from salmon has been purified (Keutmann, H. T., et al., J. Biol. Chem., 245, 1491-6 [1970]) and its structure elucidated (Niall, H. D., et. al., Proc. Nat. Acad. Sci 64, 771-8 [1969]). The material was found to be a 32 amino acid carboxyl terminal amide peptide containing a disulfide bridge between the cysteine moieties at positions 1 and 7. Using the abbreviatons CYS, SER, ASN, etc. to represent the amino acid residues, the formula for salmon calcitonin may be written as follows: ##STR1##
The burden of routinely collecting the small ultimobranchial gland of salmon from which calcitonin is obtained, the low yield of active extract obtained, and the small and rapidly diminishing size of the salmon catch, produce supply problems which cry out for a practical method for the synthesis of salmon calcitonin, or for the synthesis of substances not heretofore known which can be converted to substances having calcitonin hormonal activity. We have therefore set about to discover such methods and substances.
Although the synthesis of salmon calcitonin using classical peptide synthesis has been reported (Guttmann, S., et. al., Helv. Chim. Acta 52, 1789-1795 [1969], the art has been seeking processes which would be more practical for larger scale commercial production. Although methods are known for the synthesis of certain peptides by addition of amino acids singularly, (Merrifield, R. B., J. Am. Chem. Soc., 85, 2139-54 [1963], and Pietta, P. S. and Marshall, G. R., Chem. Commun., 650 [1970]) the synthesis of salmon calcitonin by such addition has not heretofore been reported.